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Mixed Acid-Base Disorders, Hydroelectrolyte Imbalance and Lactate Production in Hypercapnic Respiratory Failure: The Role of Noninvasive Ventilation

Claudio Terzano1, Fabio Di Stefano1, Vittoria Conti1*, Marta Di Nicola2, Gregorino Paone1, Angelo Petroianni1, Alberto Ricci1 1 Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University of Rome, Rome, Italy, 2 Laboratory of Biostatistics, Department of Biomedical Science, University ‘‘G. d’Annunzio’’ of Chieti-Pescara, Chieti, Italy

Abstract

Background: Hypercapnic Chronic Obstructive Pulmonary Disease (COPD) exacerbation in patients with comorbidities and multidrug therapy is complicated by mixed acid-base, hydro- and lactate disorders. Aim of this study was to determine the relationships of these disorders with the requirement for and duration of noninvasive ventilation (NIV) when treating hypercapnic respiratory failure.

Methods: Sixty-seven consecutive patients who were hospitalized for hypercapnic COPD exacerbation had their clinical condition, respiratory function, blood chemistry, arterial blood gases, blood lactate and volemic state assessed. Heart and respiratory rates, pH, PaO2 and PaCO2 and blood lactate were checked at the 1st, 2nd, 6th and 24th hours after starting NIV.

Results: Nine patients were transferred to the intensive care unit. NIV was performed in 11/17 (64.7%) mixed respiratory –metabolic , 10/36 (27.8%) respiratory acidosis and 3/5 (60%) mixed respiratory- patients (p = 0.026), with durations of 45.169.8, 36.268.9 and 53.364.1 hours, respectively (p = 0.016). The duration of ventilation was associated with higher blood lactate (p,0.001), lower pH (p = 0.016), lower serum sodium (p = 0.014) and lower chloride (p = 0.038). Hyponatremia without hypervolemic occurred in 11 respiratory acidosis patients. Hypovolemic hyponatremia with hypochloremia and hypokalemia occurred in 10 mixed respiratory acidosis– patients, and euvolemic hypochloremia occurred in the other 7 patients with this mixed acid-base disorder.

Conclusions: Mixed acid-base and lactate disorders during hypercapnic COPD exacerbations predict the need for and longer duration of NIV. The combination of mixed acid-base disorders and hydro-electrolyte disturbances should be further investigated.

Citation: Terzano C, Di Stefano F, Conti V, Di Nicola M, Paone G, et al. (2012) Mixed Acid-Base Disorders, Hydroelectrolyte Imbalance and Lactate Production in Hypercapnic Respiratory Failure: The Role of Noninvasive Ventilation. PLoS ONE 7(4): e35245. doi:10.1371/journal.pone.0035245 Editor: Mauricio Rojas, University of Pittsburgh, United States of America Received October 9, 2011; Accepted March 12, 2012; Published April 23, 2012 Copyright: ß 2012 Terzano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]

Introduction 40 mmHg, the ideal value of SID is 42 mmol/L . An increased SID causes alkalosis; a reduced SID causes acidosis. Altering SID Hypercapnic respiratory failure is a complex condition means altering the water dissociation equilibrium. This provides associated with the malfunction of various organs and systems more/less H+ for electroneutrality, with a change in [H+], and so a crucial for many physiological processes, leading to an acid-base change in pH. imbalance. Acid-base and electrolyte balance are part of the same picture (CO2) is not the only independent variable that because, for a given increase in CO2, the only way to minimize the may cause alterations in acid-base status. Total serum protein, resulting acidemia is to produce compensatory metabolic alkalosis, albumin in particular, plays an important role, as does the strong which is obtained through complex urinary ion excretion ion difference (SID), that is the difference between the strong mechanisms [2]. Thus, fluid depends on the correct positive ions in the plasma (sodium (Na+), potassium (K+), calcium + + relationship between lung and activities because they (Ca2 ), and magnesium (Mg2 )) and the strong negative ions + 2 2 regulate most of the CO2 and hydrogen (H ) concentrations in the (chloride (Cl ) and lactate (Lac )): extracellular volume, whose total solutes consist almost entirely of + 2 32 ÂÃNa ,Cl and ions (HCO ). { SID~ NazzKzzCa2zzMg2z {½Cl zLac{ : ð1Þ In hypoxic and hypercapnic COPD patients, fluid homeostasis is disturbed, with avid retention of sodium and water [3]. The At pH 7.4, 37uC and a partial carbon dioxide tension of increase in sodium retention by the kidneys during COPD, and

PLoS ONE | www.plosone.org 1 April 2012 | Volume 7 | Issue 4 | e35245 Mixed Acid-Base Disorders in Respiratory Failure the consequent edema, may be explained in part by right heart failure (cor pulmonale) and by other pathophysiological mecha- ðÞTBW ½1{ðÞ140=Naz : nisms involving renal and hormonal abnormalities [3,4]. In hypercapnic COPD exacerbations, the sudden decrease in Plasma osmolality was calculated using the following equation: ventilation causes an acute respiratory acidosis or deteriorates a pre-existing chronic respiratory acidosis. Due to the high ½Glucose ½BUN prevalence of comorbidities [5] and the associated multidrug 2Na½z z z : therapies in these patients, mixed acid-base and hydro-electrolyte 18 2:8 disorders are becoming increasingly common, particularly in the Because the patients’ clinical conditions did not allow us to critically ill and elderly populations. conduct reliable pulmonary function tests, the data (FVC and This study had the following aims: to evaluate mixed acid-base, FEV1) considered for the analysis were those measured subse- hydro-electrolyte and lactate disorders in patients with hypercap- quently at a stable clinical condition (or rather when vital and gas- nic COPD exacerbation; to determine the relationship among exchange parameters improved and stabilized and patients’ these disorders, a poor response to pharmacological treatment and dyspnea was not severe enough to not allow respiratory manouvres the requirement for noninvasive ventilation (NIV); and to analyze required by lung function testing). the link between these disorders and the duration of NIV in the Initially, all patients received controlled oxygen therapy with a treatment of hypercapnic respiratory failure. Venturi mask, in order to maintain an arterial oxygen saturation (SaO2) at least $90%, and conventional treatments, including Methods nebulized bronchodilators, intravenous corticosteroids, antibiotics (if necessary) and other drugs, depending on the concomitant Ethics Statement comorbidities. NIV was initiated when controlled oxygen therapy The institutional review board for human studies (Fondazione and convientional medical treatments failed to improve the clinical Eleonora Lorillard Spencer Cenci Ethics Committee) for human conditions, or rather when respiratory distress with accessory studies approved the protocol, and written consent was obtained muscle use or abdominal paradox and tachypnea (respiratory rate from the subjects or their surrogates. .24/min) were associated with persistent arterial impairment (pH,7.35, PaCO2.45 mmHg, and PaO2/FiO2,200) despite Study design optimal pharmacological treatment and oxygen therapy [7,13]. We investigated patients consecutively hospitalized in our NIV was performed via an oronasal mask using a pressure support respiratory ward (Respiratory Diseases Unit, Policlinico Umberto turbine ventilator (Polar 2 Hackermann & Bild Ltd., Crespellano, I, Rome) for COPD exacerbation and hypercapnic respiratory Bologna, Italy) with a bi-tube connection. The pressure support, failure. Between January and April 2010, sixty-seven patients were PEEP and flow-by trigger values were adjusted to obtain a tidal consecutively hospitalized for COPD exacerbation and hypercap- volume of 6–8 ml/kg and to gain the best oxygenation and reduce nic respiratory failure. COPD and COPD exacerbation were the respiratory rate. They were modified based on the blood gas defined according to the Global Initiative for Chronic Obstructive data. Heart and respiratory rates, pH, PaO2 and PaCO2 and Lung Disease (GOLD) guidelines [6]. was defined by blood lactate were checked on the 1st,2nd,6th and 24th hours after a PaCO2$45 mmHg on arterial blood gas (ABG) analysis [6]. starting NIV. Patients were excluded from this descriptive study if they had NIV was withdrawn when the clinical condition improved and concomitant pneumonia, acute lung injury (ALI) or acute stabilized, as defined by the following objective parameters: respiratory distress syndrome (ARDS), and contraindications to respiratory rate ,24/min, heart rate ,110/min, pH.7.35 and noninvasive ventilation (NIV) [7]. Patients enrolled were not SaO2.90% on FiO2,40% [14]. Patients were a priori considered necessarily at the first COPD exacerbation treated with NIV, but for invasive if the following conditions were those being on chronic NIV treatment at home were excluded. present: a worsening of arterial pH and carbon dioxide tension Comorbidities were identified on the basis of clinical records, despite correct NIV administration, an onset of coma, cardiovas- concomitant therapy, and/or investigations carried out at hospital cular instability or poor compliance with the NIV device [15]. admission. Baseline demographic characteristics and clinical parameters, Statistical analysis routine blood chemistry and ABG were assessed at admission. All quantitative variables are summarized as mean and standard The level of consciousness was assessed using the Glasgow deviation (SD), and the qualitative variables are summarized as Coma Scale [8]. The severity of the clinical condition was frequency and percentage. The results are reported separately for quantified by the Acute Physiology and Chronic Health each of the two groups (NIV use and no NIV use). The statistical Evaluation II score [9]. analysis was conducted by parametric or non-parametric test, Patients were classified into pure respiratory acidosis or mixed according to the distribution of variables as assessed by the defect (mixed respiratory acidosis–metabolic alkalosis and mixed Shapiro-Wilk test. Student’s t-test for unpaired data was used to respiratory-metabolic acidosis) categories [10]. Hypernatremia compare the quantitative variables between the two groups (NIV and hyponatremia were classified as hypovolemic, euvolemic and use and no NIV use), while the chi-squared test was used for hypervolemic [11,12], according to the clinical assessment, total qualitative variables. The unadjusted odds ratio (OR) for NIV use body water (TBW), relative body water deficit, serum urea to + + vs. no NIV use and its associated 95% confidence interval (95% creatinine ratio, serum sodium (sNa ), urinary sodium (uNa ), CI) were calculated for each variable by a logistic regression plasma osmolality (Posm) and urine specific gravity (SG). TBW analysis. One-way ANOVA for repeated measures was used with was expressed as a percentage of body weight (body weight * the clinical parameters, ABG results and lactate values to evaluate correction factor, where the correction factor was 0.6 for men, 0.5 the effects of NIV use over 24 h. Contrast analysis, a priori for women and elderly men and 0.45 for elderly women). Body specified, was used for comparisons versus previous time points. water deficit was calculated using the following equation:

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The differences in NIV duration among groups of patients for pH,7.1, hypercapnic coma or hemodynamic instability identified according to the ABG analysis values (respiratory (Figure 1). acidosis, mixed respiratory acidosis–metabolic alkalosis and mixed The enrolled COPD patients had multiple comorbidities, such respiratory-metabolic acidosis) were evaluated using the Kruskal- as hypertension (27 patients, 46.5%); ischemic heart disease (11, Wallis H test. The Mann-Whitney U test with Bonferroni 18.9%); degenerative, hypertensive and valvular heart disease (25 correction was applied to evaluate the differences of various patients, 43.1%); atrial fibrillation and other arrhythmias (18, parameters at each time point between respiratory acidosis 31%); cor pulmonale (13, 22.4%); peripheral artery disease (9, patients and mixed respiratory acidosis–metabolic alkalosis 15.5%); diabetes mellitus (17, 29.3%); chronic renal failure (20, patients. Linear regression analysis was applied to evaluate the 34.5%); and obstructive sleep syndrome (4, 6.9%). relationships between NIV duration and various parameters. Therefore they were on multidrugs treatments including diuretics, Statistical analysis was performed using SPSS Advanced ACE inhibitors, angiotensin receptor antagonists, digoxin, anti- Statistical 10.0 software (SPSS Inc., Chicago, Illinois, USA). arrhythmic drugs (such as propafenone, amiodarone, selective beta-blockers and verapamil), oral hypoglycemic agents, insulin, Results allopurinol, aspirin, statins and inhaled bronchodilators. NIV was initiated in 24 patients and succeeded in correcting Between January and April 2010, 75 patients were consecutively respiratory acidosis in all of them. The mean duration of NIV was hospitalized for COPD exacerbation and hypercapnic respiratory 42.4610.5 hours, and the mean IPAP employed was failure, but 67 were enrolled in the study population (5 patients 1664 cmH2O. Supplementary oxygen was administered during were excluded for being on chronic NIV treatment at home and ventilation, which was continuous until clinical conditions were the other 3 for the presence of concomitant pneumonia). stable with pauses for administration of conventional medications, We considered 58 of the 67 patients initially enrolled, as 9 were feeding and general care. None of the patients required the excluded because they were transferred to the intensive care unit interruption of the ventilatory assistance for discomfort, or refused the treatment. The only complications recorded were 1 case of

Figure 1. Flow chart of the consecutive COPD patients with acute hypercapnic exhacerbation enrolled in the study. doi:10.1371/journal.pone.0035245.g001

PLoS ONE | www.plosone.org 3 April 2012 | Volume 7 | Issue 4 | e35245 Mixed Acid-Base Disorders in Respiratory Failure nasal cutaneous sores and 2 cases of gastric distension, neither of Of the patients with mixed respiratory acidosis–metabolic which required interrupting the ventilatory assistance. alkalosis, 10 had hypovolemic hyponatremia, hypochloremia and Patient demographics and clinical characteristics are shown in hypokalemia due to thiazide or loop diuretic use associated with table 1. Clinical and metabolic parameters, ABG analysis, diarrhea and vomiting during a gastroenteritis episode (n = 2), electrolyte values, lactate, and urinalysis with are profuse sweating from febrile influenza syndrome (n = 4) or shown in table 2. (probably) poor dietary fluid intake (n = 4). Euvolemic hypochlor- Compared to patients undergoing standard therapy, subjects emia due to thiazide or loop diuretic use not associated with requiring NIV had a higher respiratory rate; lower PaO2, PaO2/ extrarenal hydro-electrolyte loss was detected in 7 patients with + 2 FiO2, alveolar–arterial PaO2 gradient, Na ,Cl , pH and serum mixed respiratory acidosis–metabolic alkalosis. lactate; and higher PaCO2 and blood lactate (Table 2, figure 2). In mixed respiratory-metabolic acidosis patients, the metabolic The changes in clinical parameters, ABG results and lactate acidosis was due to an exacerbation of chronic renal failure (n = 1), values during the first 24 hours of ventilation are shown in table 3. rhabdomyolysis (n = 1), in decompensated insulin- Using the ABG data and assessing the SID, we identified 36 dependent diabetes mellitus (n = 2) or metformin-related lactic patients with pure respiratory acidosis ( acidosis (n = 1 obese diabetic patient). 11.462.3 mmol/L; SID 40.761.2 mmol/L), 17 patients with mixed respiratory acidosis–metabolic alkalosis (anion gap Discussion 6 6 9.6 1.5 mmol/L; SID 49.1 2.0 mmol/L) and other 5 with Hypercapnic respiratory failure during acute COPD exacerba- mixed respiratory-metabolic acidosis (anion gap 25.963.6 mmol/ tion is an alarming event that requires careful management of the L; SID 29.261.8 mmol/L) (Figure 3). resulting respiratory acidosis. The final outcome depends on Patients with mixed respiratory acidosis–metabolic alkalosis various factors, such as the patient’s overall health status and were more likely to use NIV than those with the pure respiratory concomitant comorbidities, the baseline lung function, and the acidosis, and their NIV duration was longer (Table 4). NIV was disease severity as judged by the need for assisted ventilation and used for 3 of the patients with mixed respiratory-metabolic the degree of acidosis [16]. Our observations provide evidence that acidosis, and these patients had the longest ventilation times mixed acid-base and lactate disorders in patients with hypercapnic (Table 4). respiratory failure due to COPD exacerbation lead to the need for NIV duration was significantly associated with higher blood and longer duration of NIV. More data should be provided to + 2 lactate, lower pH and lower serum Na and Cl concentrations, as evaluate this association with combined mixed acid-base and shown by their regression coefficients (b = 17.038 and p,0.001 for hydroelectrolyte disorders. lactate, b = 2111.975 and p = 0.016 for pH, b = 20.478 and + 2 p = 0.014 for Na , and b = 20.660 and p = 0.038 for Cl ). Mixed respiratory acidosis–metabolic alkalosis In respiratory acidosis and mixed respiratory acidosis–metabolic We observed that metabolic alkalosis with hyponatremia and/ alkalosis NIV patients, heart rate, respiratory rate, pH, PaO2, or hypochloremia aggravated the respiratory acidosis due to the PaCO2 and blood lactate improved in the first 6 hours of NIV COPD exacerbation. Mixed respiratory acidosis–metabolic alka- (Figure 4), while significant improvements in the same parameters losis patients were more likely to use NIV and were subjected to th th were observed between the 6 and the 24 hour of ventilation in longer periods of ventilation compared to those with pure the mixed respiratory-metabolic acidosis patients (data not shown). respiratory acidosis. The requirement for and duration of NIV We also evaluated hydro-electrolyte balance and identified 11 was associated with low serum sodium and chloride, common respiratory acidosis patients who had normochloremic hypervol- findings in diuretic-induced metabolic alkalosis. The clinical emic hyponatremia due to chronic renal failure (n = 2), cirrhosis parameters and ABG analysis indicated more severe ventilatory (n = 1), hypothyroidism (n = 1), or chronic congestive heart failure impairment in the patients with mixed respiratory acidosis– (n = 7). metabolic alkalosis than in those with pure respiratory acidosis,

Table 1. Patients demographics and clinical characteristics.

Variables Total (n = 58) NIV use (n = 24) No NIV use (n = 34) p-valuea

Gender: Male (n, %) 43 (74.2) 18 (75) 25 (73.5) 0.028b Gender: Female (n, %) 15 (25.8) 6 (25) 9 (26.5) Age (years) 79.365.1 79.865.4 78.864.9 0.511 BMI (Kg/m2) 27.062.6 27.363.3 26.762.1 0.356 SBP (mmHg) 138.8616.9 135.8617.7 140.9616.2 0.256 DBP (mmHg) 76.768.2 74.669.8 78.266.7 0.097

FEV1 (L) 2.360.7 2.460.8 2.360.7 0.773

FEV1 (%) 57.969.9 58.669.6 57.4610.2 0.654 GCS 12.461.6 11.861.8 12.861.3 0.022 APACHE II score 17.766.2 18.467.5 17.265.1 0.477

Data expressed as Mean 6 Standard Deviation. aStudent t-test for unpaired data; b Chi-Squared Test. NIV = non invasive ventilation; BMI = Body Mass Index; SBP = Systolic Blood Pressure; DBP = Diastolic Blood Pressure; FEV1 = Forced Expiratory Volume; GCS = Glasgow Coma Scale; APACHE II score = Acute physiology and chronic health evaluation II score. doi:10.1371/journal.pone.0035245.t001

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Table 2. Patients main clinical and metabolic parameters, ABG analysis, lactate, serum electrolytes and urinalysis.

Variables Total (n = 58) NIV use (n = 24) No NIV use (n = 34) p-valuea

Glycemia (mg/dl) 139.5680.5 150.3691.2 131.9672.4 0.396 Serum albumin (g/L) 3.960.5 4.060.5 3.960.4 0.339 Serum uric acid (mg/dl) 5.762.1 5.962.5 5.661.9 0.651 Serum creatinine (mg/dl) 1.360.7 1.460.7 1.360.6 0.798 Heart rate (beats/minute) 116.7611.7 119.7612.4 114.6610.9 0.108 Respiratory rate (breaths/minute) 29.764.0 32.263.0 27.963.6 ,0.001

PaO2 (mmHg) 59.766.7 54.564.6 63.465.4 ,0.001

PaO2/FiO2 178.6638.5 160.5638.2 191.5633.6 0.002

P(A-a)O2 20.266.1 18.265.6 21.666.1 0.037 pH 7.3160.06 7.2260.04 7.3460.04 ,0.001

PaCO2 (mmHg) 68.668.3 75.665.5 63.766.2 ,0.001 Lactate (mmol/L) 1.760.2 3.160.6 0.760.2 ,0.001 2 Serum HCO3 (mmol/L) 33.667.8 35.6610.5 32.165.0 0.089 sNa+ (mmol/L) 133.469.8 129.4610.9 136.268.0 0.008 sK+ (mmol/L) 4.060.7 3.960.9 4.060.5 0.683 sCl2 (mmol/L) 98.166.1 95.066.8 100.264.5 0.001 sCa2+ (mmol/L) 1.2160.2 1.1960.1 1.2360.1 0.645 sMg2+ (mmol/L) 160.3 160.2 0.960.3 0.592 Plasma osmolality (Posm) 304.9617.9 309.7621.4 301.4614.5 0.084 uNa+ (mmol/L) 141.5687.2 123.1682.2 154.5689.4 0.178 uK+ (mmol/L) 90.3628.6 101.3632.0 85.2630.0 0.055 uCl2 (mmol/L) 168.2662.5 176.8669.8 162.1657.0 0.384 Urine specific gravity 1025.769.1 1025.669.1 1025.769.2 0.980

Data expressed as Mean 6 Standard Deviation. a Student t-test for unpaired data. ABG = arterial blood gases; NIV = non invasive ventilation; FiO2 = Fraction of inspired O2; P(A-a)O2 = alveolar-arterial PO2 gradient; sNa+ = serum sodium; sK+ = serum potassium; sCl2 = serum chloride; sCa2+ = serum calcium; sMg2+ = serum magnesium; uNa+ = urine sodium; uK+ = urine potassium; uCl2 = urine chloride. doi:10.1371/journal.pone.0035245.t002

Figure 2. Unadjusted odds ratios (OR) and 95% confidence intervals for NIV use with respect to clinical parameters, ABG results and lactate and electrolyte values that were statistically significant. NIV = noninvasive ventilation; ABG = arterial blood gases; + 2 RR = respiratory rate; P(A-a)O2 = alveolar–arterial PO2 gradient; sNa = serum sodium; sCl = serum chloride. doi:10.1371/journal.pone.0035245.g002

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Table 3. Clinical parameters, ABG analysis and lactate values at different time during NIV.

Variables 1 h 2 h 6 h 24 h p-valuea

Heart rate (beats/min) 113.4614.7 111.3614.8** 106.9616.8** 100.3617.8** ,0.001 Respiratory rate (breaths/ 29.664.9 28.564.7** 26.065.0** 22.664.4** ,0.001 min) pH 7.2660.07 7.3860.07** 7.3160.07** 7.3560.06** ,0.001 * ** * PaO2 (mmHg) 59.368.9 61.869.3 64.3610.0 66.5610.1 ,0.001 * ** ** PaCO2 (mmHg) 68.0612.2 66.5612.2 62.7612.5 59.5611.7 ,0.001 Lactate (mmol/L) 2.960.6 2.660.7** 2.160.8** 1.460.8** ,0.001

Data expressed as Mean 6 Standard Deviation. aANOVA test for repeated measures; **p,0.001; *p,0.01 contrast analysis vs previous time point. ABG = arterial blood gases; NIV = non invasive ventilation. doi:10.1371/journal.pone.0035245.t003 with the exception of those with an elevated pH due to a increase to maintain electroneutrality, which raises the central pH simultaneous alkalinizing processes. and leads to . In patients with hypercapnic respiratory failure due to COPD In addition, metabolic alkalosis has been associated with exacerbation, the presence of a sufficient metabolic compensation increased airway resistance [22]. In our study, it probably and adequate renal function significantly decreases mortality [17]. contributed to the increased respiratory impairment in the mixed In our study, the bicarbonate increase overcame the expected respiratory acidosis–metabolic alkalosis patients when compared renal compensatory response, reflecting a mixed acid-base to the subjects with pure respiratory acidosis. disorder with metabolic alkalosis due to various causes in patients In a study investigating the effects of metabolic acid-base with multiple comorbidities and undergoing multidrug treatment. changes on central ventilatory chemoregulation in normocapnic The use of diuretics for cardiovascular comorbidities was the main and hypercapnic COPD patients, the ventilatory responsiveness to cause of metabolic alkalosis with hyponatremia and/or hypo- carbon dioxide was not significantly altered by the induced chloremia. metabolic state [23]. These results may seem inconsistent with our Metabolic alkalosis causes a direct depression of the respiratory observations, but we believe that they are not comparable for drive, leads to diminished stimulation and several reasons. In the van de Ven et al. study [23], chronic metabolic acidosis and alkalosis were experimentally induced by consequently reduces alveolar ventilation to increase PaCO2 and lower pH toward normal levels [18,19,20]. the oral administration of acetazolamide and furosemide, Metabolic alkalosis is usually associated with hypochloremia, respectively, and were not caused by various comorbidities from which has a relevant inhibitory effect on the ventilatory response their multidrug treatments. The authors evaluated the responses of to hypercapnia. A reduction of serum chloride is associated with a inspired ventilation (VI) and mouth occlusion pressure (P0.1)to reduced chloride concentration in the cerebrospinal fluid [21]. changes in PaCO2, while we investigated the possible deleterious Because the cerebrospinal fluid does not contain significant weak effects of metabolic alkalosis on the ventilatory response to acids, a reduction of its chloride level will result in a bicarbonate hypercapnia by assessing the requirement and duration of NIV in a real clinical scenario.

Figure 3. Acid-base balances in patients with hypercapnic COPD exacerbation. Black lozenge: Respiratory acidosis. White square: Mixed respiratory acidosis–metabolic alkalosis; Black triangle: Mixed respiratory-metabolic acidosis. doi:10.1371/journal.pone.0035245.g003

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Table 4. Duration of NIV in groups of patients according to ABG analysis values.

Patients Overall NIV use (n, %)a Hours of NIV (Mean ± SD)b

Overall 58 24, 41.4 42.4610.5 Respiratory acidosis 36 10, 27.8 36.268.9 Mixed respiratory acidosis – metabolic 17 11, 64.7 45.169.8 alkalosis Mixed respiratory - metabolic acidosis 5 3, 60.0 53.364.1

NIV = non invasive ventilation; ABG = arterial blood gases. ap = 0.026, Chi-Squared test vs no NIV use. bp = 0.016, Kruskal-Wallis H test. doi:10.1371/journal.pone.0035245.t004

Figure 4. Trends over time in heart rate (panel A), respiratory rate (panel B), pH (panel C), PaO2 (panel D), PaCO2 (panel E) and blood lactate (panel F) during NIV. *p,0.0125, Mann-Whitney U test between groups with Bonferroni correction. NIV = noninvasive ventilation. doi:10.1371/journal.pone.0035245.g004

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The effect of metabolic alkalosis on the clinical outcome of We considered blood lactate as a diagnostic marker of tissue COPD patients was first reported in a study that showed an and respiratory muscle fatigue (lactate is a valuable energy improvement in and clinical symptoms after source within the working muscle), an indirect indicator of correcting the coexistent metabolic alkalosis [24]. hypercapnic COPD exacerbation severity and, as a consequence, Discontinuing furosemide, which is prescribed for peripheral an indirect indicator of its response to treatment. edema in patients with stable COPD, increases the minute In our study, lactate improved over time once NIV was started. ventilation and lowers the PaCO2 by correcting metabolic alkalosis Patients with higher blood lactate were more likely to require NIV [25]. Hypoventilation in response to metabolic alkalosis has serious and needed longer ventilation times. The effects of hyperlactate- implications in patients with high PaCO2 and low PaO2. COPD mia on pH were attenuated in patients with concomitant patients with a tendency toward hypercapnia require extra hypochloremic metabolic alkalosis. Therefore, acid-base analysis attention because hypercapnia is believed to be an ominous sign should not only be based on traditional parameters, such as pH, for morbidity and mortality [26,27]. The increased PaCO caused 2 2 HCO3 and the anion gap, but should rely on a more by furosemide may lead to fluid retention, which may counteract comprehensive evaluation [37]. According to Stewart [1], lactate the diuretic effects of furosemide. This is of clinical relevance, production modifies the SID and thus influences one of the especially considering that loop diuretics are prescribed to a determinants of H+ concentration. While there are tissues whose substantial number of COPD patients. Thus, other types of deranged metabolic pathways need lactate as an intermediate diuretics should be considered when diuretic therapy is indicated metabolite to survive, the production of lactate itself depends on in hypercapnic COPD patients. Spironolactone, which causes no pH [37]. Moreover, the pH controls the rate of lactate uptake acid/base shifts, or acetazolamide, which causes a metabolic from blood by hypoxic skeletal muscles [38]. acidosis, may be better options. Because loop diuretics are often necessary in COPD patients with cor pulmonale or cardiac Mixed respiratory-metabolic acidosis comorbidities, acetazolamide could be added to counteract the metabolic alkalosis [28]. In this study we identified a few patients with mixed respiratory- metabolic acidosis who required long NIV periods. Metabolic Lactate disorders acidosis stimulates hyperventilation, but these patients had impaired ventilation, probably as a result of muscle wasting due Lactate clearance, as a surrogate for the magnitude and to the metabolic academia [39]. Hospitalized patients with acute duration of global tissue hypoxia, is used for diagnostic, COPD exacerbations associated with mixed respiratory-metabolic therapeutic and prognostic purposes. The normal reference values for lactate are traditionally considered 160.5 mmol/l in normal acidosis represent more severe cases with a higher mortality rate patients and ,2 mmol/l in critically ill patients [29]. than those with the respiratory component of acidemia alone [40]. Increased lactate production indicates increased anaerobic metabolism associated with tissue hypoxia; lactate is one of the Preliminary results and further research intermediate products that increase as a consequence of In this descriptive study, we did not analyze the subgroups metabolism derangement during hypoxia [29]. derived from the combinations of mixed acid-base disorders and Lactate clearance is a useful prognostic indicator. It reveals hydro-electrolyte disturbances because the number of patients was improvements in systemic tissue hypoxia and is associated with a not sufficient to guarantee a significant statistical power for this decreased mortality rate. Patients with greater early lactate purpose clearance after 6 hours of intensive care treatment have better Probably the descriptive design of the study does not allow us to outcomes than do subjects with lower lactate clearance [30]. obtain definitive conclusions, but we strongly believe to have In addition, early lactate clearance is significantly associated investigate a field not yet explored, eventually stimulating further with decreased levels of inflammatory biomarkers, improvements prospective multicentric studies in order to completely clarify this in organ dysfunction and improved outcomes in severe sepsis and topic, which recurs frequently in clinical practice. septic shock [31]. In addition, persistently elevated lactate is Our preliminary results suggest, in fact, that in the clinical associated with a higher mortality rate [32,33]. respiratory care researchers should address the following ques- In patients with respiratory failure, the early lactate clearance tions: a) whether lactate clearance is useful during acute could be useful to assess the metabolic response to therapy and to respiratory failure to identify patients at high risk of negative identify individuals who are able to reverse the metabolic outcomes and, potentially, to increase the intensity of the derangement. Lactate clearance deserves the same diagnostic therapeutic approach; b) whether lactate clearance is predictive relevance as other noninvasive markers of delivery/consumption/ of positive outcome and could confirm to physicians that the demand mismatches. While tissue pH, O2 saturation and PCO2 current therapeutic approach is appropriate; and c) how both the can offer a precise ‘‘local’’ picture of cellular oxygen disturbance, metabolic components of mixed acid-base disorders and the lactate does not. Nevertheless, systematically checking lactate hydroelectrolyte balance alterations may worsen the hypercapnic clearance could be used to tailor the therapy in many cases of respiratory failure caused by the COPD exacerbation and may respiratory insufficiency [34,35]. affect its resolution through standard medical therapy, either alone The greatest amounts of lactate are produced by the skin, or combined with NIV. erythrocytes, skeletal muscles, and leukocytes [36]. Blood lactate concentration may only qualitatively reflect the metabolic Author Contributions phenomena occurring in the tissues. Moreover, lactate production is actually a consequence (and not the cause) of cellular acidosis. Conceived and designed the experiments: CT FDS VC AR. Performed the Because increased lactate production coincides with acidosis, experiments: FDS VC AP GP. Analyzed the data: MDN. Contributed lactate measurement is an excellent ‘‘indirect’’ marker of the reagents/materials/analysis tools: CT FDS VC GP AP AR. Wrote the paper: CT FDS VC MDN GP AP AR. metabolic condition of a cell.

PLoS ONE | www.plosone.org 8 April 2012 | Volume 7 | Issue 4 | e35245 Mixed Acid-Base Disorders in Respiratory Failure

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PLoS ONE | www.plosone.org 9 April 2012 | Volume 7 | Issue 4 | e35245